Patient Factors Influencing Dermal Filler Complications: Prevention, Assessment, and Treatment

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Open Access Full Text Article Review Patient factors influencing dermal filler complications: prevention, assessment, and treatment

Koenraad De Boulle1 Abstract: While rare, complications do occur with the esthetic use of dermal fillers. Careful Izolda Heydenrych2 attention to patient factors and technique can do much to avoid these complications, and a well-informed practitioner can mitigate problems when they do occur. Since cosmetic surgery On behalf of the Consensus is usually an elective process, requested by the patient, clinical trials are complex to organize Group and run. For this reason, an international group of practicing physicians in the field of esthetics came together to share knowledge and to try and produce some informed guidance for their 1Aalst Dermatology Group, Aalst, colleagues, considering the literature and also pooling their own extensive clinical experience. Belgium; 2Cape Town Cosmetic Dermatology Centre, Century This manuscript aims to summarize the crucial aspects of patient selection, including absolute City, South Africa contraindications as well as situations that warrant caution, and also covers important considerations for the pre- and posttreatment periods as well as during the procedure itself. Guidance is given on both immediate and long-term management of adverse reactions. The majority of complications are related to accepting patients inappropriate for treatment or issues of sterility, placement, volume, and injection technique. It is clear that esthetic practitioners need an in-depth knowledge of all aspects of treatment with dermal fillers to achieve optimal outcomes Video abstract for their patients. Keywords: dermal fillers, complications, prevention, assessment, treatment, patient factors

Introduction A wide range of dermal fillers is now available for use in facial esthetics.1 All are potentially capable of causing complications,2,3 but fortunately, serious occurrences are rare, although probably underreported. Careful attention to patient selection, education, and injection technique can minimize the incidence of complications, and an understanding of the early signs of complications and their proactive management can decrease their impact. Point your SmartPhone at the code above. If you have a Selecting appropriate patients, or perhaps more importantly, not treating inappropri- QR code reader the video abstract will appear. Or use: http://dvpr.es/1G2e9Uh ate patients, is the first and a crucial step in avoiding complications with dermal fillers. This review considers the factors that should be borne in mind when assessing a patient for suitability for dermal filler treatment. It aims to give the practitioner an overview of contraindications, preventative measures, recognition of events, and appropriate treatment options. There remains, however, no consensus on the best treatment for adverse reactions, and each treatment option with its advantages and disadvantages should be carefully considered and discussed with the patient.4 Correspondence: Koenraad De Boulle Aalst Dermatology Group, Cosmetic surgery is usually an elective process, requested by the patient. As such, Leopoldlaan, 43, 9300 Aalst, Belgium clinical trials are complex to organize and conduct. For this reason, an international Tel +32 53 781 899 Email [email protected] group of practicing physicians in the field of cosmetic surgery came together to share

submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2015:8 205–214 205 Dovepress © 2015 De Boulle and Heydenrych. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted http://dx.doi.org/10.2147/CCID.S80446 without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php De Boulle and Heydenrych Dovepress knowledge and to try and summarize what is published and of an underlying mental disturbance or dysmorphophobic produce some informed guidance for their colleagues. This tendency. manuscript is the result of preparation, study, and discussion Well-focused pretreatment photographs should be taken, among the group and is based on the literature as well as the not only for assessment of treatment effects and any adverse group’s clinical experience. The authors acknowledge that effects but also for medicolegal purposes.5,6 this guidance is based on the collective experience of the The patient’s medical history and subsequent evaluation group at the time of writing, but it is not definitive, and there must be comprehensive, and patients should be advised is a paucity of previously published data in many areas. to include cosmetic treatments when giving their history. de Bree et al7 reported on a patient who received polyacryl- Methods amide gel and developed a paranasal granuloma. The authors The first author regularly receives queries and referrals relat- emphasized that the patient did not disclose her cosmetic ing to complications with dermal fillers, with an increasing treatment history, which confounded the diagnosis. proportion originating from outside the major EU countries. The suitability of different fillers needs to be discussed, A round table meeting was convened with interested physi- and the patient given an indication of the likely value that can cians from some of these countries to discuss adverse events be obtained from treatment.2,6 Soft tissue augmentation is an associated with dermal filler treatments and the training elective procedure, and not all those seeking treatment may requirements for injectors. be suitable candidates on medical grounds. It is important to Patient selection emerged as a core topic of concern, avoid treating patients who have preexisting conditions that and in the light of the lack of information, the delegates clearly mandate against the use of dermal fillers Table( 1). wished to collate their experience in avoiding complications. This is a crucial and often neglected area of esthetic practice. Subsequently, the authors developed this consensus paper Other patients may be somewhat dubious candidates, where based on those discussions and a review of the current treatment must be at the discretion of the physician whose literature. informed judgment is paramount. PubMed and Ovid Medline databases were searched using A convenient way of considering patient-related factors terms of “complications” OR “soft filler complications” OR is as skin-related or systemic factors. A clear link needs “injectable complications” AND “dermal fillers”. Papers to be made between the two to ensure that the patients are from 2005 were selected (although older papers may be forthcoming about all conditions or treatments, even if they referred to in discussions where relevant). References cited believe them to be completely unrelated. in selected articles were also reviewed to identify additional Firstly, contraindications detailed in the instructions for relevant reports. use of the chosen filler should be closely adhered to. These Because of the nature of esthetic procedures, where mainly refer to the product constituents or excipients; patients patients are not referred, but elect to have treatment by the with multiple or severe allergies and those with a history of practitioner of their own choosing, it is challenging to devise anaphylaxis should not be treated. meaningful clinical trials. Some authors have conducted Similarly, where data are available on a particular product prospective trials, but these are the minority of studies or technique, the physician should take care not to extrapolate and are often not randomized or controlled. Therefore, our the results or assume that they are transferrable. This includes knowledge base comprises case reports and summaries of results obtained only in one area of the anatomy.8 individual practitioner’s experience. This underlines the need Prospective patients with abnormally thin skin or skin to gather consensus views from experienced injectors who atrophy, such as seen in corticosteroid-induced atrophy of the have treated many patients. skin due to long-term topical or peroral steroid use, or with conditions such as anetoderma, vermiculate atrophoderma, or Pre-procedure considerations rheumatoid arthritis-associated skin thinning of the dorsum Patients’ expectations must be managed, so they do not of the hands, are not suitable candidates for superficial or envisage an unrealistic outcome, and they must be made medium-depth placement of certain fillers. Very thin skin aware of the limitations and risks of dermal fillers. The treat- on the eyelids and in cheeks that have many fine wrinkles is ment of inadequately informed patients can be fraught with also a contraindication for certain fillers.9 problems and may cause dissatisfaction.5 Caution should be Infections in, or adjacent to, the region to be treated can exercised when confronting an individual who exhibits signs be exacerbated and cause complications, since the infecting

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Table 1 Conditions contraindicating or warranting caution in the use of dermal fillers Condition Examples or comment CI PD NAC Active skin infection Impetigo, herpes simplex, massive demodex folliculorum, X pityrosporum, Propionibacterium acnes, viral warts Inflammatory conditions of the skin Atopic patients, allergic contact dermatitis, “status cosmeticus” or X sensitive skin syndrome, seborrheic dermatitis, active lichen planus, active acne rosacea Other inflammatory diseases Pyoderma X Osteoarthritis Active localized infection Ear, nose, or throat infections, dental abscess, periodontitis X Active generalized infection Gastroenteritis, urinary bladder infection X Noninfectious gastrointestinal Crohn’s disease, ulcerative colitis X conditions Allergy/hypersensitivity Hypersensitivity to filler components including lidocaine, chronic X urticaria, and Quincke’s edema Active psoriasis arthropatic If condition is more arthropatic: caution warranted X X If condition is more psoriatic than arthropatic: treatment is possible Systemic infections: viral HIV X Conditions potentially causing a Lichen planus, lichen nitidus, or lichen sclerosus, psoriasis, viral warts X Koebner response Active collagenoses Mixed connective tissue disease X Active morphea, active systemic lupus Other collagenoses Marfan syndrome, Ehlers–Danlos syndrome X Stabilized morphea X Immune compromise Graft versus host disease X Immune compromise Bullous diseases X Autoimmune conditions Active Hashimoto’s disease X Mixed connective tissue disease Autoimmune conditions Dermatomyositis/polymyositis, lupus erythematosus, rheumatoid X arthritis Transplant patients Heart, kidney, liver, bone marrow transplant: beware of increased risk X Immunosuppressive therapy of infections Thyroid dysfunction Not a contraindication to treatment, but physician needs to be aware X that eyelid swelling is common (unrelated and unprovoked by filler use) Metabolic disorders Diabetes, porphyria X Catabolic status X Cachexic state Does not contraindicate treatment, but product may be more visible X in patients who lack subcutaneous fat and have thin tissue coverage Conditions affecting skin Melasma and post-inflammatory hyperpigmentation X pigmentation Skin pigmentation/depigmentation Fitzpatrick Types 5 and 6 skin, vitiligo, and albinism X Systemic infections: bacterial Tuberculosis X Active anticoagulant medication Thrombolytics X Hemostatic or coagulation Hemophilia, hemoglobin pathology, thalassemia X disorders Cutaneous collagenoses Chronic discoid lupus erythematosus, active but not end-stage X scleroderma Food intolerance X Bariatric gastric sleeve surgery Potentially reduced time of esthetic effect X Abbreviations: CI, contraindicated; PD, treat at physician’s discretion; NAC, no apparent contraindication. organism may populate the site of filler use. Thus, any patient pityrosporum folliculitis. The presence of excessive amounts with an ongoing skin infection in the area intended to be treated of Propionibacterium acnes or parasitic mite infections, such or in the close vicinity of it should not be treated.10 These condi- as massive demodex folliculorum infestation, also makes the tions include the following: viral infections such as herpes sim- patient an unsuitable candidate for treatment. plex virus (HSV) and perioral human papilloma virus (HPV); Active inflammatory dermatitis, including atopic der- mollusca contagiosa; bacterial infections with streptococci or matitis, allergic contact dermatitis, “status cosmeticus”, or staphylococci, such as impetigo; yeast infections; and extensive seborrheic dermatitis, also cautions against treatment, and

Clinical, Cosmetic and Investigational Dermatology 2015:8 submit your manuscript | www.dovepress.com 207 Dovepress De Boulle and Heydenrych Dovepress physicians must make a judgment based on the severity of granulomatosis, transplant patients, patients with inflamma- the condition and its proximity to the treatment area. tory bowel disease (Crohn’s disease or ulcerative colitis), When active HSV is evident, treatment should be substantial food intolerance, repetitive urinary infections or deferred, and a prophylactic agent (acyclovir, valaciclovir, impaired renal or hepatic function, thyroid dysfunction, and or famciclovir) prescribed to prevent reactivation and spread cachectic or catabolic status need careful consideration on of HSV because of injection trauma. When treating the a case-by-case basis. perioral area and lips, prophylactic prescribing to patients Disorders of hemostasis or coagulation, for example, with known history of HSV episodes should be considered coagulopathies, protein C deficiency, hemophilia, and to prevent virus reactivation.2,11 hemoglobin disorders such as thalassemia, need a careful Patients may attend for treatment of one facial area while assessment, and an accurate clinical picture of their severity harboring an infectious condition in another (eg, active fol- and management must be obtained. liculitis with pustules), assuming that the infected area will Immune depression or suppression is not necessarily not affect their treatment. There is little guidance, and to our a contraindication to any type of filler,9 although poly-l- knowledge, there are no published studies assessing the pos- lactic acid should be avoided.10 Clinical experience suggests sible sequelae of treating individuals with active infection, hyaluronic acid fillers to be safe in patients with porphyria regardless of distance from the treated area. (Meissner, personal communication). Patients with infections such as sinusitis, periodontal dis- A full medical treatment history is essential, and although ease, ear, nose, or throat infections, or dental abscesses should there are no defined interactions, certain immunosuppressive not be treated until the condition has resolved.12 Increasingly, agents and steroids should flag up the need to understand clinical evidence is emerging indicating that these infections the patient’s medical history more clearly. Even agents that might subsequently invade implanted filler areas, inducing interfere with cytochrome P450 should be considered as biofilm reactions. Later, transition from infection to an estab- signals to proceed with caution. lished hypersensitivity, via toll-like receptors, is possible, Patients should be advised to stop anti-inflammatory and since these molecules have been shown to be involved in antiplatelet agents a week prior to treatment (if medically the development of many pathological conditions, includ- appropriate) to minimize bruising, and they may benefit from ing infectious diseases, tissue damage, and autoimmune and a list of foodstuffs, herbal supplements, and over-the-counter neurodegenerative diseases.13 medications to avoid.14–16 Dermal filler treatment can also aggravate more general- Although there is weak evidence that antiplatelet therapy ized skin conditions or connective tissue disease, or might may be continued safely in the perioperative period,17 there not be suitable in some of these conditions. Examples include are few publications addressing the issue systematically, and prominent scars, hypertrophic scarring and keloid, bullous esthetic practitioners are warned to be mindful of the bleeding diseases, pyoderma, cutaneous collagenoses (chronic discoid risk that applies to individual patients.18 Patients with cardio- lupus erythematosus or lupus erythematosus, active but not vascular stents or taking anticoagulants in the long term need end-stage scleroderma), Marfan syndrome, Ehlers–Danlos careful consideration, and the risks must be explained.6 syndrome, mixed connective tissue disease, conditions that Although the most commonly used hyaluronic acid-based cause Koebner response such as lichen planus (and related products have a favorable safety profile, adverse events can conditions), and active psoriasis. Uncontrolled immune and do occur. Mild and self-limiting complications are rela- deficiencies, such as graft versus host disease, chronic urti- tively common. Edema and bruising are more or less inevi- caria, and Quincke’s edema, may also be adversely affected table, and these mild events resolve quickly.2,6,12 Although by dermal filler injection, or conversely might affect the bruising tends to occur more extensively with certain injec- behavior of the filler in the tissue. tion techniques, such as fast injection, aggressive fanning, Dermal fillers are not contraindicated in patients in whom high-volume filler deposits, or large bolus injections (more wound healing is normal, even though they may have an than 0.5 mL per bolus), all sensible precautions should be underlying systemic disease. No association has been estab- taken with any injection technique.19,20 lished between use of fillers and autoimmune conditions. Thus, patients with HIV, rheumatoid arthritis, diabetes, Timing of other cosmetic procedures or scleroderma who have normal wound healing may be Botulinum toxin treatment should be planned 2 weeks prior treated.9,10 Conditions such as tuberculosis, Wegener’s to filler. Using botulinum toxin first can help in assessment

208 submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2015:8 Dovepress Dovepress Complications of dermal fillers of the need for treatment of residual issues such as static Patients should understand the need to take precautions lines and deep folds that can be treated with hyaluronic acid and be scrupulously clean after treatment, such as avoiding fillers.21 From a safety perspective, however, the treatments touching and keeping hair away from the treated area for may be given on the same day. several hours. Patients should not use cosmetics (especially Microdermabrasion, chemical peels, and intense pulsed lipstick post-lip enhancement) for 24 hours and use new light (IPL) should ideally be carried out 1–2 weeks pre- or containers of lotions and new/clean brushes, sponges, etc.15,23 posttreatment and fractional resurfacing 3–4 weeks dis- The patient should be willing and able to attend a consulta- tant to allow erythema to diminish and the skin barrier to tion 2–4 weeks after any procedure and should report any reestablish. One small pilot study, however, compared injec- concerns or signs of problems as soon as possible. tion of hyaluronic acid-based filler immediately followed by laser, radiofrequency (RF), or pulsed light treatments (IPL) Proactive prevention to injection of filler alone. The results suggested that laser, recommendations RF, and IPL may be safely administered immediately after Injectors need to have a thorough knowledge of facial hyaluronic acid gel implantation. Data suggest that deeper anatomy and the potential danger areas, especially the dis- filling immediately before laser therapy, when the concomi- tribution of the facial arteries and nerves.3 However, text- tant swelling may facilitate the effect of the laser, may be book anatomy is representative of the general population, acceptable.9 Using biodegradable or temporary fillers over and subtle individual variations are relatively common,24,25 permanent fillers has always been a heavily debated subject. warranting continuous caution upon injecting fillers and Lemperle et al stated that temporary fillers may be injected awareness of the possibility of perforating, lacerating, or on top of a permanent filler or can be used preceding the compromising vessels. Patients with a history of dental or permanent filler with no interference between the two and facial surgery may have areas of unusual vascular distribution that fear of a second filler inducing granuloma formation because of aberrant neovascularization after the trauma of a remains hypothetical.9 The present authors, however, would procedure in combination with a decrease in tissue laxity.26 strongly discourage this practice, as it is generally accepted It is of paramount importance that any material placed under that the formerly called “permanent” fillers (now referred to the skin is injected under sterile conditions using aseptic as late or minimally biodegradable fillers) are associated with technique. The patient’s skin should be cleaned, degreased, substantially more frequent and late-occurring side effects, and disinfected. There are no universally recommended topi- sometimes occurring years after implantation. cal antiseptics, but chlorhexidine, chloxylenol, iodophors, When one type of filler is used on top of, or around, alcohol, and iodine may all be appropriate.6,15,23 Rarely, the other, and a side effect emerges, it is impossible to a patient may experience an allergic reaction to cleansers and determine the causal agent without biopsy, specific pathol- topical anesthetic agents, and physicians need to recognize ogy staining, and examination of the sample. Moreover, the signs and immediately remove the product responsible the duration, prognosis, and eventual treatment options of from the skin. Patients may also be allergic to the lidocaine the side effects may be completely different for the two mixed in the syringe of the filler.10 types of filler. Caution is also needed – albeit to a lesser The injector should wash his/her hands thoroughly, extent – when injecting over surgically inserted solid remove watches and rings, and wear surgical gloves (although implants (eg, expanded polytetrafluoroethylene or polylactic not necessarily sterile).15 Areas of irritation or inflammation acid plates and screws). should not be injected, needles or cannulas must be sterile and To avoid possible infection or hypersensitivity, treatment changed frequently during the procedure, excess filler on the should not be undertaken in the immediate period following syringe needle should only be removed with sterile gauze,6,15 other routine medical procedures (including vaccination).12 and aseptic technique followed throughout the procedure. Dental procedures should be performed at least 2 weeks Treatment areas should not be reinjected within 2 weeks of the pre- or posttreatment to minimize the risk of hematogenous initial procedure. Even with perfect tissue integration, a cer- bacterial spread and potential development of biofilm. tain level of edema and extravasation of blood can be present Chlorhexidine mouthwash prior to perioral injections (lips, in the early postinjection phase, creating an ideal environment borderline mucosal, or oral cavity approach of injection) will for bacteria to proliferate upon repeated injection. reduce oral bacterial flora for 8 hours, also minimizing the Before injecting, aspiration should be performed as a risk of contamination when lip licking.22 prophylactic measure,6 particularly in highly vascularized

Clinical, Cosmetic and Investigational Dermatology 2015:8 submit your manuscript | www.dovepress.com 209 Dovepress De Boulle and Heydenrych Dovepress areas, and a new needle without filler used prior to deep later, and red/bluish coloration is indicative of venous bolus injections. Blood on aspiration indicates that the occlusion.27 Other secondary (and later stage) diagnostic needle is in a blood vessel and the injection point should be symptoms are blisters and pustules, tissue necrosis (which altered. Injection must be performed slowly and with caution, generally develops a few days after the initial complica- allowing time to assess and react to any untoward response, tion), and scarring, which is the end stage of the necrosis changes in skin color, or disproportionate pain.6,27,28 and healing process. Filler should be injected slowly with a low flow rate in When vascular occlusion is suspected, it is vital that the small quantities at multiple points and overfilling avoided.20 injection is stopped immediately and treatment is rapidly Small-bore needles are recommended by some to slow instigated. The goal is to promote blood flow to the affected the injection rate27 and blunt needles/cannulas in high-risk area, which may be achieved by applying a warm compress, regions to reduce vessel injury.29,30Avoiding anesthesia with massaging or tapping the area, and applying 2% nitroglycerin epinephrine (adrenalin) close to a vascular bundle to prevent paste to promote vasodilatation.6,27,28,36 Attempts should be vasospasm and tenting the skin to avoid the vascular supply made to dissolve or eliminate the injected product. In the are also appropriate recommendations.16 case of hyaluronic acid-based fillers, hyaluronidase should To prevent the technique-related problems of irregulari- be injected all over the affected area, “flooding the area with ties, lumps, or beading, injection technique and depth should hyaluronidase”, as soon as possible in a dose applicable to the be appropriate for the area being injected and the area mas- product to be reversed, for example, 10–20 units per injec- saged after injection.28 Accidental intramuscular injection tion point.26,32 If a hydroxyapatite filler has been used, saline of synthetic fillers other than hyaluronic acid and collagen could be injected. Hyaluronidase has been suggested as a should be avoided, since muscle contraction can dislocate treatment for all cases of vascular compromise, regardless the filler and create unwanted lumps.9 of filler employed, since it can reduce edema and potentially decrease vessel-occluding pressure.3,37 It is important to Recognition and treatment be aware that hyaluronidase has been associated with rare recommendations – early events immediate and delayed reactions, and prescribing guidelines Vascular occlusion should be closely followed.38,39 Vascular occlusion can occur if a filler is injected into a blood It may be possible to use ultrasound or MRI to assess the vessel or when sufficient quantity is injected near the vessel location and amount of filler, and Doppler; arteriography or to cause a compression blockage.14,31,32 The two types are arte- phlebography may help in assessing vascular damage and rial (generally an acute onset – during injection) and venous aid treatment planning. (generally a delayed onset – often when the patient has left Hyaluronidase (or alternative) injections should be the clinic), although the two are not mutually exclusive.6,26 repeated on a daily basis where appropriate and continued Arterial occlusion is the more serious complication and for at least 4 days or as long as there are signs of ischemia.27 can potentially be very damaging, leading to ischemia, tissue However, some evidence suggests that after day 1, any addi- degradation, and necrosis. In rare cases, it can even cause tional effect is minimal.26 visual impairment or blindness if it affects the retinal artery. An anticoagulant, such as low-molecular weight heparin, The underlying mechanism is related to retrograde embo- aspirin, clopidogrel, or pentoxifylline, could also be pre- lization from peripheral vessels into the ophthalmic arterial scribed to increase blood flow to the wound. Other authors system.33–35 This makes it vital for the clinician to be aware have suggested the use of sildenafil to dilate compromised of the early warning signs to facilitate quick diagnosis and vasculature.3 an immediate, aggressive response.3,27 Antibiotics (oral and/or topical) and antivirals are rec- The two primary diagnostic symptoms of vascular occlu- ommended to reduce infection in the case of pustule/blister sion are pain and changes in skin color. Immediate, severe, formation. In severe cases, hyperbaric oxygen could be used and disproportionate pain and acute onset of color changes – to aid survival of compromised tissue. blanching (or white spots/blotches) – are an indication of Classic wound care procedures (wet-to-dry dressings, arterial occlusion.27 Venous occlusion may be associated petroleum gauze with 3% bismuth tribromophenate, emol- with less severe, dull, or delayed pain; in some cases, there lients, debridement, etc) should be followed, and the patient may be no pain (this is rare in the case of arterial occlusion). assessed for scar evaluation and management. Surgery and Skin color changes may be immediate or up to 3–4 hours reconstruction may be indicated at a later date.16

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In cases of visual impairment, the individual should to differentiate between anaphylaxis and angioedema, as the undergo an urgent ophthalmologic consultation.33 Orbital latter or localized urticaria do not cause alteration in vital pain and visual disturbance may be managed with additional signs. However, even progressing angioedema can become ocular massage, timolol maleate eye drops, diuretics, corti- a medical emergency due to airway obstruction. Any sys- costeroids, hemodilution, vasodilation, anticoagulation, or temic manifestations should be considered as impending thrombolysis as required under expert guidance.37 anaphylaxis and treated as such. Resuscitation equipment should be available at the clinic or nearby. Epinephrine Allergic/hypersensitivity reactions (adrenalin) should be administered immediately, intravenous Hypersensitivity and allergic reactions such as angioedema access obtained, and fluid resuscitation considered. Hospital can occur when the injected dermal filler (or an agent used admission may be advisable for severe cases, as late-phase in gel production or injection procedure) triggers an immune reactions may occur up to 36 hours after the initial event. It response.6,9,14 This can be a type I hypersensitivity reaction, remains important that the “triggering” substance is removed which typically has an early onset (within minutes to hours if at all possible, and hyaluronidase may be used where of injection), or a type IV reaction, which has a delayed onset appropriate. (1–3 days up to several weeks after injection).31 Although Additional vasopressor agents should be considered not demanding the urgent attention that vascular occlusion (dopamine, norepinephrine, and glucagon) if the above requires, it can be a problem that causes considerable patient measures are insufficient to maintain perfusion. H1-receptor distress.2 antagonists (in combination with cimetidine) could be used The primary diagnostic symptoms of hypersensitivity for histamine-induced hypotension, oral corticosteroids reactions may include edema (either localized around injec- administered to prevent late-phase reactions, and inhaled tion sites or more generalized), erythema, pruritus, pain or bronchodilators given if respiratory symptoms are noted. tenderness (related to pressure effects), rash, and induration.2,14 Localized angioedema and urticaria should be managed Delayed reactions may also present with various types of skin by cold compresses and H1-receptor antagonist administra- lesions40 including painful erythematous nodules.31 tion to reduce pruritus.2 The value of additional H2-receptor Once a hypersensitivity reaction is suspected, the time antagonists and leukotriene synthesis inhibitors should be of onset should be established, the patient’s medical history considered. Twice daily dosing with histamine blockers may re-reviewed, and a full medical examination undertaken. In be required for the symptomatic management of histamine cases of diagnostic uncertainty, special investigations include release. It is not uncommon for higher than normal doses blood tests such as markers for inflammation (C-reactive to be required. Propranolol and ibuprofen have both been protein [CRP], erythrocyte sedimentation rate [ESR]) and advocated in reducing persistent erythema. acute-phase reactants. The latter appear to be the most Additional treatment options include topical or intral- sensitive markers for the presence of autoimmune/inflam- esional steroids, or immunosuppressive agents (under matory syndrome induced by adjuvants (ASIA) related to specialist supervision). These include hydroxychloroquine, dermal filler use. A biopsy (if a previously used product is of methotrexate, ciclosporin A, diaminodiphenylsulfone, and unknown type), MRI, or ultrasound (high frequency) should allopurinol.2,42 be considered. A study of responses to a wide range of dermal fillers Recognition and treatment demonstrated that calcium hydroxyapatite, methacrylate, recommendations – delayed events acrylamides, and silicone produced notable chronic activa- Infection tion of the immune system (mediated by macrophages and Any procedure that breaks the surface of the skin carries polymorphonuclear leukocytes). By contrast, hyaluronic with it a risk of infection, and injecting dermal fillers is acid elicited little immune response.41 The plasma levels of no exception. Treatment-related infections are generally myeloperoxidase and the chitin-like proteins chitotriosidase bacterial (but can be fungal or viral). They can be broadly and YKL-40 may be important markers indicative of immune categorized as acute infections, which appear as acute inflam- response activation in certain cases. mation or abscesses at the site of injection (typically due to Hypersensitivity reactions can be severe, and occasionally, common pathogens present on the skin such as Staphylococ- anaphylactic shock has been reported.14 Generalized edema cus aureus or Streptococcus pyogenes), or delayed-onset, is suggestive of anaphylaxis; vital signs should be checked chronic infections, which generally develop 2 or more weeks

Clinical, Cosmetic and Investigational Dermatology 2015:8 submit your manuscript | www.dovepress.com 211 Dovepress De Boulle and Heydenrych Dovepress after injection. Delayed-onset infections tend to affect a more to establish their etiology and confirm the diagnosis. They generalized area and may involve an atypical organism (such may be inflammatory or non-inflammatory in nature and as Mycobacteria or Escherichia coli). Insidious late infection related or unrelated to infection. Historically, nodules tend or biofilm can also occur.31,43 These are challenging for both to be described as granulomata without the histopathologi- diagnosis and treatment and can cause a chronic inflamma- cal evidence. tory response. Early-onset nodules – occurring within 4 weeks – tend The primary diagnostic symptoms of infection are ery- to be painless and non-inflammatory, and are most likely thema, warmth, tenderness, pain, swelling (usually at or close the result of suboptimal techniques such as excess filler to site of injection), local signs of abscess (pustules, nodules, use, superficial placement, and incorrect product for the areas of fluctuation, crusts), and systemic fever. It is prudent indication.1,9,15,27 These early-onset nodules tend to occur to be highly suspicious of any area near the site of injection in areas of thin soft tissue coverage. Early red, painful, and exhibiting local symptoms. Differentiation between infec- tender nodules usually signal a concomitant infection. tion and hypersensitivity is important during diagnosis, as Delayed-onset nodules (after 4 weeks and up to a year or the use of steroids should be avoided in infection. Important longer) are more likely to be inflammatory (immune responses differentiating factors which indicate infection are skin to the filler material) and/or infection related (includ- temperature, pain (absent, more diffuse, or less intense in ing biofilm) but may just be persistent non-inflammatory cases of hypersensitivity), fever or signs of an abscess, and nodules.2,27,31,47,48 If nodules are biofilm related, a culture test the absence of pruritus. will frequently be negative. It is therefore important to use The time of injection in relation to time of onset, blood polymerase chain reaction or fluorescence in situ hybridiza- tests, or infective markers (such as CRP, ESR, and procal- tion tests for delayed-onset nodule complications where citonin) may be diagnostically useful, and purulent material biofilm involvement is suspected.31 Delayed-onset nodules may be cultured to determine the type of pathogen and the may also result from the incorrect use of fibroblast stimula- most appropriate antibiotic. tory fillers (eg, polylactic acid, calcium hydroxyapatite) in Acute, mild infections can be treated with oral antibiotics.43 areas where skin is thin or mobile. Empiric treatment should begin with macrolide or tetracy- Foreign body granulomas may form as the body’s cline antibiotics, which may have some anti-inflammatory and immune system responds to a foreign body that cannot be immunomodulatory effects.14,27 Two-drug therapy should be broken down by the usual mechanisms. They can develop considered to broaden the spectrum of cover. Hyaluronidase several months, or even years, after injection and present as has been shown to help break down the matrix, decreasing any red, firm papules, nodules, or plaques. Diagnosis of nodules associated biofilm mass,44 and other options are prolonged and lumps is further complicated by the fact that clinicians are or intravenous antibiotics, intralesional 5-fluorouracil, or sometimes faced with patients with unknown or incomplete laser45,46 and surgical drainage of any abscess. Examples medical and cosmetic treatment history. of antibiotic courses that are typically prescribed to treat The therapeutic approach will be determined by the type complicated infections are as follows: of lumping/nodule diagnosed. Early-onset nodules should be • Ciprofloxacin 500–750 mg bid for 2–4 weeks treated by massage, application of a compress, and punctur- • Clarithromycin 500 mg + moxifloxacin 400 mg bid ing of the nodule if appropriate. If a hematoma is present, for 10 days early pressure and heat, and then cold compress should be • Vancomycin IM 600–1,000 mg five times every sec- applied.27 For both early- and late-onset nodules, disruption ond day, followed by 300–500 mg od for 10 days with hyaluronidase, lidocaine, or saline followed by massage • A quinolone at 500 mg bid for up to 50 days can be effective. If the nodule is infection related and there is • Minocycline 100 mg od for 6 months fluctuance or impending signs of erosion, incision and drain- • Cephalexin, dicloxacillin, or nafcillin age should be performed with culture and antibiotic cover • Topical antibiotics – fucidic acid. continued for up to 4–6 weeks.27 Hypersensitivity-related nodules may be treated with antihistamines (eg, cetirizine, Nodule formulation and loratidine), oral steroids (eg, medium-dose pulse therapy granulomatous reactions prednisolone, 60 mg/day), methyl prednisolone (eg, a total of Nodules and lumps are common complications resulting 240 mg in six weekly decreasing doses), and/or nonsteroidal from the use of dermal fillers. Careful assessment is required anti-inflammatory drugs2 once infection has been ruled out.

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RF or infrared energy may also be a useful adjunctive treat- Russia; Marshall Murdoch, Albertus Niemann, Daniel Nortje, ment option in some areas.47 Martina van der Mescht, South Africa; Tunc Tiryaki, Gun For late-onset nodules or granulomas, intralesional Ersu, Ulvi Guner, Alpalan Topcu, Serhan Tuncer, Turkey; steroids (betamethasone 5 mg/mL or triamcinolone Oleksamdr Turkevych, Ukraine. 10–40 mg/mL for 10 days up to 4 weeks) can be considered, although care needs to be taken to avoid skin atrophy.2,4 Disclosure For persistent cases, additional measures can include a The authors report no conflicts of interest in this work. series of injections of 5-fluorouracil (50 mg/mL) in combination with steroids and/or lidocaine (1:3), methotrexate, 2,4,49 References local tacrolimus, cortivasol, allopurinol, colchicine, isot- 1. Requena L, Requena C, Christensen L, Zimmermann US, Kutzner H, retinoin, imiquinod,49 laser-assisted removal,45 or ultimately Cerroni L. Adverse reactions to injectable soft tissue fillers.J Am Acad 12 Dermatol. 2010;64:1–34. excision by surgery as a last resort. 2. De Boulle K. Management of complications after implantation of fillers. J Cosmet Dermatol. 2004;3:2–15. 3. Funt D, Pavicic T. Dermal fillers in aesthetics: an overview of adverse Summary and conclusion events and treatment approaches. Clin Cosmet Invest Dermatol. 2013;6: The wide range of dermal fillers available for use in facial 295–316. esthetics makes it essential to have a thorough knowledge of 4. Sperling B, Bachmann F, Hartmann V, Erdmann R, Wiest L, Rzany B. The current state of treatment of adverse reactions to injectable fillers. the relevant product characteristics. Clinicians must have a Dermatol Surg. 2010;36:1895–1904. sound understanding of facial anatomy and be suitably trained 5. Vedamurthy M, Vedamurthy A, Nischal KC. Dermal fillers: do’s and and experienced to ensure correct product selection, prepara- dont’s. 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